Multiparticulates are well-known dosage forms that comprise a multiplicity of particles whose totality represents the intended therapeutically useful dose of a drug. When taken orally, multiparticulates generally disperse freely in the gastrointestinal tract, maximize absorption, and minimize side effects. See, for example, Multiparticulate Oral Drug Delivery (Marcel Dekker, 1994), and Pharmaceutical Pelletization Technology (Marcel Dekker, 1989).
A typical multiparticulate formulation consists of a drug substantially uniformly distributed in a carrier. A conventional process for producing such multiparticulates is to add the drug and carrier to a heated tank to produce a molten mixture that is then atomized into droplets and the droplets congealed to form the multiparticulates. This process is capable of forming small, round, smooth multiparticulates in which the drug is encapsulated in the carrier. However, conventional pharmaceutical manufacturing processes typically require a mean residence time of the drug in the molten mixture of several hours or longer for economical production of the multiparticulates. For some drugs, such long mean residence times can lead to rapid drug degradation or to undesirable reactions of the drug with the carrier. Because of this, conventional pharmaceutical melt-congeal processes are not considered useful for preparing multiparticulates of labile drugs.
It is also known to form multiparticulates using other processes which do not form a molten mixture, such as extrusion spheronization or wet granulation. However, such processes often result in multiparticulates in which the drug is not completely encapsulated in the carrier. Moreover, such processes may result in multiparticulates that have irregular or rough exterior surfaces. Such multiparticulates may have poor flow properties and may be difficult to coat. In addition, irregular and rough multiparticulates present a gritty sensation in the mouth.
U.S. Pat. Nos. 6,261,599 and 6,335,033 disclose a controlled release dosage form comprising an opioid analgesic and a carrier. The analgesic and carrier are blended and then heated to a temperature sufficiently high to extrude the blend into a strand having a diameter of from 0.1 to 3 mm. The strand is then cooled and divided to form multiparticulates. There is no disclosure of the use of an atomizer to form multiparticulates from the extrudate, nor is there any recognition of improved chemical stability obtained by using an extruder to form the molten mixture.
U.S. Pat. No. 6,248,363 discloses a spray-congeal process for forming free-flowing drug-containing powders from melts. The drug is allowed to melt, disperse, or dissolve in a hot melt of a carrier and is then atomized into an air chamber wherein the temperature is below the melting point of the components, thereby providing spherical congealed pellets. The process is stated to be suitable for heat labile substances since ambient temperature is used to dry the pellets. However, there is no disclosure of the use of an extruder to produce a molten mixture to be atomized, nor is the need for minimizing the mean residence of the drug in the molten mixture to improve chemical stability.
U.S. Pat. No. 5,824,342 discloses solloids consisting of a solid suspension of a solid non-fat substrate having an active ingredient associated therewith, the non-fat substrate and the active being non-uniformly dispersed in a solid fat carrier. The solloids may be made by a “flash shear” process wherein the temperature of a feedstock material is raised to a point where the carrier undergoes intraparticle flow. The flash shear process is stated to be a “cold flow” process that has no long residence times in the carrier and so avoids the problems associated with a heat history created by long residence times.
U.S. Pat. No. 6,139,872 discloses an extrusion process for producing a nutritional supplement powder consisting of forming a feedstock into a plastic mass that is not completely molten, then shaping, cooling and comminuting the plastic mass to obtain the powder.
U.S. Pat. No. 5,100,592 discloses a process for forming particles from a powdery material wherein the powdery material is discharged onto a heated rotary spreader. A portion of the powdery material is melted on the rotary spreader, coating non-melted particles, which are then discharged as larger particles from the periphery of the rotary spreader.
U.S. Pat. No. 4,086,346 discloses a method for melt-spraying the thermally sensitive drug phenacetin alone by means of a multi-screw extruder having extremely tight clearances between the screw shafts and between the screws and the housing, the extruder melting the drug, delivering the molten drug to an atomizer for atomizing and cooling and solidifying the melt-sprayed drug.
U.S. Pat. No. 5,766,521 discloses a process for melt-congealing crystallized pearls of the drug glyceryl guaiacolate, whereby the drug is melted, atomized, then cooled to below the drug's glass transition temperature to form pearls, placing the so-formed pearls into contact with crystallization seeds and then crystallizing the pearls by heating.
Published U.S. Patent Application No. 2001/0006650 discloses solid solution beadlets of drug, a fatty acid or ester and a surfactant formed by spray-congealing, consisting of mixing drug particles in the melted fatty acid or ester, then spraying the resulting mixture into a spray-congeal tower having cool air flowing through the tower to solidify the beadlets. However, there is no disclosure of the use of an extruder to form a drug/carrier molten mixture, nor any suggestion of a solution to the problem of degradation of labile drugs used in the process.
There is therefore a need in the art for an efficient melt-congeal process of forming multiparticulates containing labile drugs wherein drug degradation is kept to an acceptably low level during the process, and which results in multiparticulates that are smooth, round, and in which the drug is substantially encapsulated in the carrier.